Genetic Variant NM_001088.3:c.468C>T (chr17-76469814-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001088.3(AANAT):c.468C>T(p.Ala156Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,604,098 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 38 hom. )

Consequence

AANAT
NM_001088.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.04

Variant links:

Genes affected

AANAT (HGNC:19): (aralkylamine N-acetyltransferase) The protein encoded by this gene belongs to the acetyltransferase superfamily. It is the penultimate enzyme in melatonin synthesis and controls the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for the function of the circadian clock that influences activity and sleep. This enzyme is regulated by cAMP-dependent phosphorylation that promotes its interaction with 14-3-3 proteins and thus protects the enzyme against proteasomal degradation. This gene may contribute to numerous genetic diseases such as delayed sleep phase syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

AANAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 17-76469814-C-T is Benign according to our data. Variant chr17-76469814-C-T is described in ClinVar as [Benign]. Clinvar id is 714416.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.04 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00181 (2632/1451750) while in subpopulation EAS AF= 0.0305 (1198/39244). AF 95% confidence interval is 0.0291. There are 38 homozygotes in gnomad4_exome. There are 1299 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AANAT	NM_001088.3 link	c.468C>T	p.Ala156Ala	synonymous_variant	Exon 4 of 4	ENST00000392492.8	NP_001079.1	Q16613-1F1T0I5
AANAT	NM_001166579.2 link	c.603C>T	p.Ala201Ala	synonymous_variant	Exon 7 of 7		NP_001160051.1	Q16613-2
AANAT	NR_110548.2 link	n.724C>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AANAT	ENST00000392492.8 link	c.468C>T	p.Ala156Ala	synonymous_variant	Exon 4 of 4	1	NM_001088.3	ENSP00000376282.2		Q16613-1

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

336

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0173

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0175

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00326

AC:

748

AN:

229192

Hom.:

AF XY:

0.00305

AC XY:

383

AN XY:

125410

show subpopulations

Gnomad AFR exome

AF:

0.0000720

Gnomad AMR exome

AF:

0.0000303

Gnomad ASJ exome

AF:

0.000420

Gnomad EAS exome

AF:

0.0165

Gnomad SAS exome

AF:

0.000486

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.000853

Gnomad OTH exome

AF:

0.00372

GnomAD4 exome

AF:

0.00181

AC:

2632

AN:

1451750

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

1299

AN XY:

721430

show subpopulations

Gnomad4 AFR exome

AF:

0.0000901

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.000387

Gnomad4 EAS exome

AF:

0.0305

Gnomad4 SAS exome

AF:

0.000791

Gnomad4 FIN exome

AF:

0.0189

Gnomad4 NFE exome

AF:

0.000236

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00221

AC:

337

AN:

152348

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

226

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.0175

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0175

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000778

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.34

DANN

Benign

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over